Adequate and Appropriate Donor Screening Tests for Hepatitis B; Hepatitis B Surface Antigen (HBsAg) Assays Used to Test Donors of Whole Blood and Blood Components, Including Source Plasma and Source Leukocytes: Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Guidance for Industry
Adequate and Appropriate Donor
Screening Tests for Hepatitis B;
Hepatitis B Surface Antigen (HBsAg)
Assays Used to Test Donors of Whole
Blood and Blood Components,
Including Source Plasma and Source
Leukocytes
Additional copies of this guidance document are available from the Office of Communication,
Training and Manufacturers Assistance (HFM-40), 1401 Rockville Pike, Rockville, MD 20852-
1448, or by calling 1-800-835-4709 or 301-827-1800, or from the Internet at
http:www.fda.gov/cber/guidelines.htm.
For questions on the content of this guidance, contact the Division of Emerging and Transfusion
Transmitted Diseases at 301-827-3008.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
November 2007
This guidance updates the July 2007 guidance of the same title to extend the
implementation date.

Contains Nonbinding Recommendations
Table of Contents
I. 	INTRODUCTION................................................................................................................. 1
II. 	BACKGROUND ................................................................................................................... 2
III. RECOMMENDATIONS...................................................................................................... 3
IV. 	IMPLEMENTATION .......................................................................................................... 4
V. 	REFERENCES...................................................................................................................... 4
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Contains Nonbinding Recommendations
Guidance for Industry
Adequate and Appropriate Donor Screening Tests for Hepatitis B;
Hepatitis B Surface Antigen (HBsAg) Assays Used to Test Donors of
Whole Blood and Blood Components, Including Source Plasma and
Source Leukocytes
This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this
topic. It does not create or confer any rights for or on any person and does not operate to bind
FDA or the public. You can use an alternative approach if the approach satisfies the
requirements of the applicable statutes and regulations. If you want to discuss an alternative
approach, contact the appropriate FDA staff. If you cannot identify the appropriate FDA staff,
call the appropriate number listed on the title page of this guidance.
I. 	INTRODUCTION
Blood establishments are required under 21 CFR 610.40(a)(3) and (b) to test donations of human
blood and blood components for hepatitis B virus using approved screening tests that are
adequate and appropriate for this purpose. One test used to detect the presence of hepatitis B
infection is the hepatitis B surface antigen (HBsAg) test. This document provides
recommendations to manufacturers of HBsAg assays that are intended to be used to test donors
of Whole Blood and blood components, including Source Plasma and Source Leukocytes, and to
establishments using an HBsAg assay. This guidance represents the Food and Drug
Administration’s (FDA’s) current thinking on minimum sensitivity standards for such HBsAg
assays, as they relate to testing “to reduce adequately and appropriately the risk of transmission
of communicable disease” under 21 CFR 610.40(b) (see Section III). Under 21 CFR 610.44,
manufacturers of test kits used to test donations for hepatitis B virus must use a reference panel
from FDA or an FDA-designated source when such panel is available and appropriate to verify
acceptable sensitivity and specificity of such kits (see Ref. 1). This guidance document finalizes
the draft guidance document entitled “Guidance for Industry: A Modified Lot-Release
Specification for Hepatitis B Surface Antigen (HBsAg) Assays Used to Test Blood, Blood
Components, and Source Plasma Donations” dated April 2002.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the FDA’s current thinking on a topic and should be
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.
The use of the word should in FDA’s guidances means that something is suggested or
recommended, but not required.
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Contains Nonbinding Recommendations
II. 	BACKGROUND
Since 1975, we, FDA, have distributed Reference Hepatitis B Surface Antigen panels to
manufacturers of HBsAg detection assays used to test donors of Whole Blood and blood
components, including Source Plasma and Source Leukocyte donations. Manufacturers use
these panels, suitable for testing HBsAg assays of so-called “third generation” sensitivity (mostly
radioimmunoassays and enzyme immunoassays), to test manufactured kit lots of HBsAg
detection assays for screening Whole Blood and blood components, including Source Plasma
and Source Leukocytes, to ensure a minimum sensitivity for those kit lots. FDA also distributes
the panels to unlicensed manufacturers who are developing such HBsAg assays. The panels are
used to test the sensitivity of HBsAg assay lots, pre- and post-licensure, under our lot-release and
surveillance programs.
The current Center for Biologics Evaluation and Research’s (CBER’s) panel, distributed since
1996, contains 10 plasma samples: eight reactive and two nonreactive for HBsAg. The eight
reactive samples are estimated to contain about 0.02, 0.04, 0.5, 0.9, 1.0, 2.5 to 3.0, 5.0 to 6.0 and
7.0 to 8.0ng HBsAg/mL (see footnote to the table on page 3, under Section III.). The current
lower limit of detection specification for HBsAg assays used to test blood donations corresponds
to 1.0ng HBsAg/mL. The CBER panel sample estimated to contain about 1.0ng HBsAg/mL is
detected by all HBsAg test kit lots used to test Whole Blood and blood components, including
Source Plasma and Source Leukocyte donations.
Since this 1.0ng HBsAg/mL sensitivity specification for HBsAg assays was implemented, we
acquired information that the different HBsAg detection assays, both licensed and investigational
assays that are developed for eventual licensure, varied widely in relative sensitivity below this
limit. Furthermore, we learned that some of these assays might have detection capabilities well
below 1.0ng HBsAg/mL.
Therefore, we initiated a study comparing three (at that time) investigational and four licensed
HBsAg detection assays and procedures, to evaluate whether newer HBsAg assays were more
sensitive than the then-used licensed methods. The rationale for performing such a study was to
ascertain whether newer assays might increase the capability of detecting donations that are
potentially infectious for hepatitis B virus. Since that time, FDA has licensed all three
previously investigational assays.
At a Blood Products Advisory Committee (BPAC) meeting held on March 15, 2001 (Ref. 2),
preliminary data generated by FDA and industry were presented which indicated that the
sensitivity of HBsAg licensed and investigational assays varies significantly. In particular, the
lower limit of detection ranged from 0.07 to 0.13ng HBsAg/mL for the three investigational
assays (all of which are now licensed) and for one licensed assay tested. On the other hand, a
detection limit range from 0.27 to 0.62ng HBsAg/mL was observed for three licensed assays
tested. Based on these observations, we asked BPAC whether the HBsAg donor screening
assays should be capable of a lower limit of detection. BPAC voted in favor of a lower limit of
detection, with 14 “yes” votes, 0 “no” votes and 0 abstentions.
2

Contains Nonbinding Recommendations
Taking BPAC’s recommendation into consideration, we are recommending that assays used
under 21 CFR 610.40(b) to test Whole Blood and blood components, including Source Plasma
and Source Leukocyte donations have a capability of detecting at least 0.5ng HBsAg/mL.
HBsAg assays that do not have this capability should not be used to test Whole Blood and blood
components, including Source Plasma and Source Leukocyte donations, because FDA believes
that tests that are incapable of identifying HBsAg at these limits are not adequate to reduce the
risk of communicable disease transmission. If more HBsAg assays demonstrate greater
capability to detect HBsAg at even lower levels, we will reconsider this recommendation.
III. 	RECOMMENDATIONS
We recommend that establishments using HBsAg detection assays to test Whole Blood and
blood components, including Source Plasma and Source Leukocyte donations, use assays that
have a lower limit of detection capability of 0.5ng HBsAg/mL or less in order to reduce
adequately and appropriately the risk of transmission of communicable disease. HBsAg assays
that do not have this capability should not be used to test Whole Blood and blood components,
including Source Plasma and Source Leukocyte donations, because FDA believes that they are
not adequate or appropriate for this purpose. FDA recommends that test kits that are used to test
Whole Blood and blood components, including Source Plasma and Source Leukocyte donations,
employ the following performance standard when testing the CBER HBsAg Lot-Release Panel
#12:
Panel Sample
1201
Estimated Concentration
of HBsAg (ng/mL)
1.0
Expected Reactivity*
+
1202 	5.0 to 6.0 	+
1203 	0 	–
1204 	0.04a +
1205 	0.5 	+
1206 	0 	–
1207 	2.5 to 3.0 	+
1208 	7.0 to 8.0 	+
1209 	0.02a +
1210 	0.9 	+
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Contains Nonbinding Recommendations
* + = reactive; + = reactive or non-reactive; – = non- reactive
a <0.1 ng/mL; imputed value shown is based on dilutions
IV. 	IMPLEMENTATION
We recommend implementation of these recommendations on July 31, 2008.
V. 	REFERENCES
1. 	Requirements for Testing Human Blood Donors for Evidence or Infection Due to
Communicable Disease Agents; Final Rule, June 11, 2001 (66 FR 31146).
- 21 CFR 610.40.
- 21 CFR 610.44.
2. 	Blood Products Advisory Committee Transcript, March 15, 2001.
(http://www.fda.gov/ohrms/dockets/ac/01docsbc.htm).
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